NM_002063.4:c.115T>C

Variant names:

• chrX-14532285-T-C
• rs867583605
• NM_002063.4:c.115T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_002063.4(GLRA2):​c.115T>C​(p.Ser39Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,189,077 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: GLRA2 NM_002063.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.44
• Publications: 0 publications found

Genes affected

GLRA2 (HGNC:4327): (glycine receptor alpha 2) The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

GLRA2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked, syndromic, Pilorge type

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.7002 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, X-linked, syndromic, Pilorge type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15941074).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002063.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA2	NM_002063.4	MANE Select	c.115T>C	p.Ser39Pro	missense	Exon 2 of 9	NP_002054.1	P23416-1
	GLRA2	NM_001118885.2		c.115T>C	p.Ser39Pro	missense	Exon 3 of 10	NP_001112357.1	P23416-1
	GLRA2	NM_001118886.2		c.115T>C	p.Ser39Pro	missense	Exon 2 of 9	NP_001112358.1	P23416-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA2	ENST00000218075.9	TSL:1 MANE Select	c.115T>C	p.Ser39Pro	missense	Exon 2 of 9	ENSP00000218075.4	P23416-1
	GLRA2	ENST00000355020.9	TSL:1	c.115T>C	p.Ser39Pro	missense	Exon 2 of 9	ENSP00000347123.4	P23416-2
	GLRA2	ENST00000415367.2	TSL:3	n.366T>C		non_coding_transcript_exon	Exon 2 of 9

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111770 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1077307 Hom.: 0 Cov.: 23 AF XY: 0.00000290 AC XY: 1 AN XY: 344715

African (AFR) AF: 0.0000387 AC: 1 AN: 25868

American (AMR) AF: 0.00 AC: 0 AN: 34807

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19058

East Asian (EAS) AF: 0.00 AC: 0 AN: 29893

South Asian (SAS) AF: 0.00 AC: 0 AN: 52567

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4072

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 825440

Other (OTH) AF: 0.00 AC: 0 AN: 45294

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111770 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33990

African (AFR) AF: 0.0000324 AC: 1 AN: 30859

American (AMR) AF: 0.00 AC: 0 AN: 10509

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52965

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.35	N
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.91	P
Vest4		0.24
MutPred		0.23		Gain of catalytic residue at P38 (P = 0.0133)
MVP		0.91
MPC		1.4
ClinPred		0.28	T
GERP RS		4.9
Varity_R		0.20
gMVP		0.72
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs867583605; hg19: chrX-14550407;